Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])(=O)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+].[C:28](Cl)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]>O1CCOCC1.O>[C:28]([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCN(CCCC)C(C(=O)O)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCN(CCCC)C(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of compound (80) is dissolved in 30 mL of dioxane, and 10 mL of 6N hydrochloric acid solution is added, and the solution is refluxed overnight. The reaction is cooled to room temperature, concentrated to dryness, redissolved in 30 mL of tetrahydrofuran, and 10 mL of water and 30 mmol of sodium bicarbonate is added, followed by 15 mmol of Fmoc-Cl. The biphasic solution is stirred for 1 hour, and the tetrahydrofuran removed under vacuum. The aqueous solution is extracted with 1×50 mL of diethyl ether, acidified with 1N hydrochloric acid solution, and extracted with 2×50 mL of ethyl acetate. The ethyl acetate layers are combined, dry over sodium sulfate, and concentrated. Compound (81) is purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:13])[CH3:12].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CC(C)Oc1cccc(N)c1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1C(=O)Nc1cccc(OC(C)C)c1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid, 15.1 g (0.1 mol) of m-isopropoxyaniline and 10.1 g (0.1 mol) of triethylamine were dissolved in 100 ml of xylene. A 5.1 g (0.033 mol) amount of phosphorus oxychloride was added dropwise to the prepared solution with stirring at 90° - 100° C. Stirring of the resulting solution was continued at 90° - 100° C for 3 hours. The reaction mixture was cooled and washed with water, and the product was dried over anhydrous sodium sulfate. The xylene was removed to obtain 20.9 g (77.9%) of white prismatic crystals having a melting point of 92°-94° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH:13][CH2:14][CH3:15])[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([NH:13][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:27])[F:16])[CH:19]=2)[N:7]=[C:6]([C:8]#[N:9])[C:5]=1[N+:10]([O-:12])=[O:11])[CH3:15]
Reactant: CCNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCNc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)c1[N+](=O)[O-]
Yield: 64.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (2.78 g) was added under a nitrogen atmosphere to a mixture of 6-chloro-4-ethylamino-3-nitro-pyridine-2-carbonitrile (10.9 g), 4-trifluoromethyl-phenylboronic acid (10.0 g) in degassed dioxane (500 mL) and a 2M aqueous solution of potassium carbonate (60 mL). The mixture was refluxed for 4 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: DCM then DCM/acetone 95/5) to afford the title compound (10.4 g, 64%). 1H NMR (DMSO-d6) δ: 8.59 (br. s, 1H); 8.50-8.40 (m, 2H); 7.91 (d, J=8 Hz, 1H); 7.79 (t, J=7 Hz, 1H); 7.74 (s, 1H); 3.65 (q, J=7 Hz, 2H); 1.24 (t, J=7 Hz, 3H). MS m/z: 337 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CO[C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1N1CCNCC1>>[CH2:2]1[C:37]2[C:36](=[CH:42][CH:41]=[C:39]([NH:40][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:38]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc(N)cc1N1CCNCC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(methyloxy)-3-(1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.90 (s, 8H), 3.72 (s, 3H), 6.43 (d, 1H, J=5.3 Hz), 6.80 (d, 1H, J=8.8 Hz), 7.09 (t, 1H, J=6.5 Hz), 7.22 (d, 2H, J=8.1 Hz), 7.25 (d, 1H, J=3.9 Hz), 7.32 (t, 2H, J=8.3 Hz), 7.45 (q, 2H, J=7.9 Hz), 7.58 (quintet, 1H, J=8.3 Hz), 7.79 (d, 1H, J=8.2 Hz), 7.99 (s, 1H), 8.18 (d, 2H, J=5.7 Hz), 8.43 (bd, 1H, J=8.3 Hz), 8.81 (d, 1H, J=6.8 Hz), 9.26 (s, 1H), 10.92 (s, 1H); ESIMS (M+H)+=633.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.CS(O[CH2:33][CH2:34][CH3:35])(=O)=O.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[CH2:33]([NH:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1)[CH2:34][CH3:35]
Reactant: CCCOS(C)(=O)=O
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCN[C@@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@@H]1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 27.9 %

Procedure:
Into 2 ml of DMF were dissolved 200 mg (0.68 mmol) of cis-3-amino-4-methyl-1-(1-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride and 0.11 ml (0.81 mmol) of triethylamine, and 188 mg (1.36 mmol) of n-propyl methanesulfonate was added under ice cooling. Then, the mixture was stirred for 5 hours at room temperature, for 3 hours at 60° C. and further for 5 hours at 70° C. After addition of water, the solution was made alkaline with sodium bicarbonate, which was then extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crude oil. This was subjected to silica gel column chromatographic purification (methylene chloride:methanol=20:1) to obtain 57 mg (27.9%) of aimed compound (pale yellow oil).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[CH:8]=2)[NH:3]1>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:8]=2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(=O)N3)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 4-(2-oxoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (912 mg, 2.90 mmol) in THF (10 ml) and MeOH (10 ml) was added 10% Pd/C (453 mg) and stirred at room temperature under H2 (1 atom) atmosphere for 7 h. The reaction mixture was filtered through a Celite pad and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to afford tert-butyl 4-(2-oxoindolin-5-yl)piperidine-1-carboxylate (846 mg, 92%).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([OH:21])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid ethyl ester (2.33 g, 7.9 mmol) was dissolved in 40 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (828 mg, 19.8 mmol) was added. After stirring overnight at room temperature, the volatiles were removed under vacuum and 75 ml of water was added to the mixture, which was brought to pH 2 with 1N HCl. The resulting slurry was extracted with 2×100 ml of ethyl acetate, the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated under vacuum to provide 2.15 g of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:40][CH2:39][C:33]2([C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:41])[F:42])=[CH:32][CH:31]=3)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: NCC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1(c2ccc(C(F)(F)F)cc2)CCCCC1)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-{1-[4-(trifluoromethyl)-phenyl]cyclohexyl}methanamine (57 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is filtered. The solid is washed well with water and dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (1H, s), 8.78 (2H, d, J 4.8), 7.65 (2H, d, J 8.4), 7.55 (2H, d, J 8.4), 7.31 (1H, t, J 4.8), 6.27 (1H, bs), 3.63 (2H, d, J 6), 2.17 (2H, m), 1.77 (2H, m), 1.66 (2H, m), 1.42 (4H, m). MS (M+1)=464.14; RT=1.37 min. *IC50.
Reaction SMILES: [CH:1]1CCCCC=1.[CH3:7][O:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1C#C[Si](C)(C)C)=[O:10].[C:27]([O-:30])(O)=[O:28].[Na+].OO>C1COCC1>[CH3:7][O:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:1][C:27]([OH:30])=[O:28])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)c1c(C#C[Si](C)(C)C)ccc2ccccc12
Reactant: O=C([O-])O
Reactant: C1=CCCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(CC(=O)O)ccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
21 ml (0.22 Mol) borane dimethylsulfide complex are added dropwise during 15 min to an ice-cooled solution of 50.2 ml (495 mMol) cyclohexene in 400 ml of THF. The mixture is stirred for 2.5 h at rt and again cooled in an ice-bath. Then a solution of 23.29 g (82.5 mMol) trimethylsilanylethynyl-naphthalene-1-carboxylic acid methyl ester in 400 ml of THF is added dropwise. The mixture is warmed up to rt and stirred for 1 h. Then 585 ml sat. NaHCO3 solution and 138 ml H2O2 (30% in H2O) are added slowly (cool to keep temperature below 60° C.). The suspension is stirred for 16 h and then concentrated in vacuo. The residue is diluted with 1 l sat. NaHCO3 solution, 375 ml water and EtOAc, the organic layer is separated off and washed with 0.5 l sat. NaHCO3 solution and 250 ml water and discarded. The aq. phases are acidified by addition of 4 N HCl (pH=2) and extracted with 3 portions of EtOAc. The organic layers are dried (MgSO4) and concentrated. Trituration from hexane affords the title compound: MS: [M+1]+=245; HPLC: tRet=12.3.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=[CH:14][N:13]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[C:17]([C:2]2[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Reactant: CSc1cc(I)nc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nccnc2F)nc(C)n1
Temperature: 140 °C
Yield: 11.9 %

Procedure:
A glass microwave reaction vessel was charged with 4-iodo-2-methyl-6-(methylthio)pyrimidine (266 mg, 1.000 mmol), 2-fluoro-3-(tributylstannyl)pyrazine (387 mg, 1.000 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) in toluene (3 mL). The reaction mixture was stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 4-(3-fluoropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (28 mg, 0.119 mmol, 12% yield). 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H); 8.32 (s, 1H); 7.67 (s, 1H); 2.79 (s, 3H); 2.63 (s, 3H). m/z (ESI, +ve ion) 237.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(Cc1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 77.4 %

Procedure:
A suspension of 9 mg of (Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-5-yl}-acrylic acid in 2 ml of methanol and 1 ml of dichloromethane and 6 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (2 h). The mixture was filtered, the filtrate evaporated and the residue was purified by HPLC (RP-18, CH3CN/H2O, gradient) to give 7 mg of the title compound as a colorless oil. MS: (M−H)− 403.3.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][NH2:17].[C:18]([C:21]([N:27]([CH3:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][CH:31]=1)=[O:29])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23])(O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[I:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]([N:27]([CH3:37])[C:21]([CH3:26])([C:18]([NH:17][O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[O:19])[C:22]([NH:24][CH3:25])=[O:23])=[O:29])=[CH:35][CH:34]=1
Reactant: NOC1CCCCO1
Reactant: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (0.11 mL) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (24 mg) were added to a DMF (5.0 mL) solution of 1-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 11, 81 mg) and HATU (120 mg) under ice cooling, and the mixture was stirred for 2 hours at room temperature. Water was added, and the mixture was extracted with chloroform. Then, the organic layer was washed with brine, and dried over magnesium sulfate. The desiccant was filtered out, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with chloroform/methanol=100/0→95/5) to obtain 2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 12, light yellow oil) (59 mg, 57%).
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:19])(=O)=O.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([Cl:19])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCSc2ccccc2C1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-Acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (10 g) was dissolved in methylene chloride (150 ml) and sulfuryl chloride (9.3 g) was added thereto under ice cooling and agitated at 0° C. for 1 hour. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.5 g).
Reaction SMILES: ClC1C=CC=C(Cl)N=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([Cl:28])[N:20]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([Cl:28])[N:20]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(=O)N1CCNCC1
Agent: Clc1cccc(Cl)n1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: CC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
2,6-Dichloropyridine is nitrated with fuming nitric acid and concentrated sulfuric acid. The product, 2,6-dichloro-3-nitropyridine, is allowed to react with N-acetyl-piperazine in chloroform to give 2-(4-acetyl-1-piperazinyl)-6-chloro-3-nitropyridine (m.p. 137°-138° C.). The compound obtained is treated with aqueous ammoniaethanol in an autoclave to give 2-(4-acetyl-1-piperazinyl)-6-amino-3-nitropyridine (m.p. 202°-203° C.), which is then acetylated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-acetyl-1-piperazinyl)-3-nitropyridine (m.p. 189°-193° C., 221°-223° C.).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16]3=[C:17]4[C:12](=[CH:11][CH:10]=[C:9]([N:25]([C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:27]=5)[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:8]4=[CH:7][CH:6]=2)[CH:13]=[CH:14][C:15]=13
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccc2ccc3c(N(c4ccccc4)c4ccc5ccccc5c4)ccc4ccc1c2c43
Temperature: 100 °C
Yield: 36.9 %

Procedure:
A mixture of 18 g (50 mmol) of 1,6-dibromopyrene, 11 g (50 mmol) of N-phenylnaphthalen-2-amine, 0.16 g (0.7 mmol) of Pd(OAC)2, 0.5 g (1.4 mmole) of tri-tert-butylphosine, 6 g (75 mmol) sodium tert-butoxide was stirred in 200 ml dry toluene, the reaction mixture was then heat to 100° C. for about overnight under nitrogen. The solution was filtered. The toluene solution was removed under reduced pressure from the filtrate. The residue was extracted three times with dichloromethane and water, dried with MgSO4 and filtered, and the dichloromethane was removed under reduced pressure. The product was purified by column chromatography to get 9.2 g of product (yield 37%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([CH3:26])([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]2[O:21]C(C)(C)C(C)(C)[O:18]2)=[CH:13][CH:12]=1)[CH3:9])(C)(C)C.[O:29]1CC[CH2:31][CH2:30]1.O>C(O)(=O)C.C1(C)C=CC=CC=1>[C:30]([O:6][CH2:7][C:8]([CH3:9])([CH3:26])[O:10][C:11]1[CH:12]=[CH:13][C:14]([B:17]([OH:18])[OH:21])=[CH:15][CH:16]=1)(=[O:29])[CH3:31]
Reactant: C1CCOC1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCC(C)(C)Oc1ccc(B(O)O)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of tert-butyl(dimethyl){2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}silane (5.0 g) in acetic acid (30 mL)-tetrahydrofuran (10 mL)-water (10 mL) was stirred for 2 days. The reaction mixture was diluted with toluene and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), pyridine (2.4 mL), acetic anhydride (1.5 g) and N,N-dimethyl-4-aminopyridine (0.1 g) were added and the mixture was stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 30 min, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in 1 M hydrochloric acid (10 mL)-tetrahydrofuran (10 mL)-water (10 mL), sodium periodate (3.2 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give the title compound as a pale-yellow solid (1.6 g, 52%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:36]([O:35][C:33]([N:31]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OCc1ccccc1)C1CCCC1

Procedure:
{2′-[(Benzyloxycarbonyl-cyclopentyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-35) was prepared by following the procedures of Example 1 and using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclopentylamine, and benzyl chloroformate.